The invention relates to benzoylguanidines of the formula I ##STR2## in which: R(1) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or NR(7)R(8);
R(7) and R(8) are, independently of one another, hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms PA2 R(25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF.sub.3, CH.sub.3, methoxy, hydroxyl, amino, methylamino and dimethylamino; PA2 R(25) is --(C.sub.1 -C.sub.9)-heteroaryl, which is unsubstituted or substituted by I - 3 substituents selected from the group consisting of the group F, Cl, CF.sub.3, CH.sub.3, methoxy, hydroxyl, amino, methylamino and dimethylamino; PA2 R(26) and R(27) are, independently of one another, defined as R(25) or are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; PA2 m is zero, 1 or2; PA2 R(14) is --(C.sub.3 -C.sub.8)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F and Cl, --CF.sub.3, methyl, methoxy and --NR(15)R(16); PA2 R(32), R(33) and R(34) are, independently of one another, hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; PA2 R(7) and R(8) are, independently of one another, hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; PA2 R(25) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, CF.sub.3, CH.sub.3, methoxy and dimethylamino; PA2 R(25) is --(C.sub.1 -C.sub.9)-heteroaryl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, CF.sub.3, CH.sub.3, methoxy and dimethylamino; PA2 R(26) and R(27) are, independently of one another, hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; PA2 m is zero, 1 or2; PA2 R(14) is --(C.sub.3 -C.sub.6)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, --CF.sub.3, methyl and methoxy; PA2 R(32), R(33) and R(34) are, independently of one another, hydrogen or methyl; PA2 R(25) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or phenyl, which is unsubstituted or substituted by one substituent selected from the group consisting of F, Cl, CF.sub.3 and CH.sub.3 ; PA2 R(25) is --(C.sub.1 -C.sub.9)-heteroaryl, which is unsubstituted or substituted by one substituent selected from the group consisting of F, Cl, CF.sub.3 and CH.sub.3 ; PA2 R(26) and R(27) are, independently of one another, hydrogen or methyl; PA2 R(32), R(33) and R(34) are, independently of one another, hydrogen or methyl; PA2 R(25) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or phenyl, which is unsubstituted or substituted by one substituent selected from the group consisting of F, Cl, CF.sub.3 and CH.sub.3 ; PA2 R(25) is --(C.sub.1 -C.sub.9)-heteroaryl, which is unsubstituted or substituted by one substituent selected from the group consisting of F, Cl, CF.sub.3 and CH.sub.3 ; PA2 R(26) and R(27) are, independently of one another, hydrogen or methyl;
R(2) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or --SO.sub.2 R(9) R(9) is independently defined as R(1); PA1 R(3) is hydrogen, --SR(25), --OR(25), --NR(25)R(26) or --CR(25)R(26)R(27); PA1 R(4) is hydrogen, F, Cl, Br, I, OH, --C.tbd.N, CF.sub.3, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms or --(CH.sub.2).sub.m R(14); PA1 R(5) and R(6) are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, --OR(32), --NR(33)R(34) or CF.sub.3 ; PA1 R(1) is alkyl having 1, 2, 3 or 4 carbon atoms or NR(7)R(8); PA1 R(2) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or --SO.sub.2 R(9) R(9) is independently defined as R(1); PA1 R(3) is hydrogen, --SR(25), --OR(25), --NR(25)R(26) or --CR(25)R(26)R(27); PA1 R(4) is hydrogen, F, Cl, Br, I, OH, CF.sub.3, alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms or --(CH.sub.2).sub.m R(14); PA1 R(5) and R(6) are, independently of one another, hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, Cl, --OR(32), --NR(33)R(34) or CF.sub.3 ; PA1 R(1) is methyl or dimethylamino; PA1 R(2) is hydrogen, methyl, --SO.sub.2 CH.sub.3 or --SO.sub.2 N(CH.sub.3).sub.2 ; PA1 R(3) is hydrogen, --SR(25), --OR(25), --NR(25)R(26) or --CR(25)R(26)R(27); PA1 R(4) is hydrogen, F, Cl, OH, CF.sub.3 or alkyl having 1, 2, 3 or 4 carbon atoms; PA1 R(5) and R(6) are, independently of one another, hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, Cl, --OR(32), --NR(33)R(34) or CF.sub.3 ; PA1 R(1) is methyl or dimethylamino; PA1 R(2) is hydrogen; PA1 R(3) is hydrogen, --OR(25) or --CR(25)R(26)R(27); PA1 R(4) is hydrogen, OH, CF.sub.3 or alkyl having 1, 2, 3 or 4 carbon atoms; PA1 R(5) and R(6) are, independently of one another, hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, Cl or CF.sub.3 ;
or
R(15) and R(16) are, independently of one another, hydrogen or --CH.sub.3 ;
and their pharmaceutically acceptable salts.
Preferred compounds of the formula I are those in which:
or
and their pharmaceutically acceptable salts.
Particularly preferred compounds of the formula I are those in which:
or
and their pharmaceutically acceptable salts.
Very particularly preferred compounds of the formula I are those in which:
or
and their pharmaceutically acceptable salts.
The specified alkyl radicals can be present both straight-chain and branched.
(C.sub.1 -C.sub.9)-Heteroaryl means radicals which are derived from phenyl or naphthyl in which one or more CH groups are replaced by N and/or in which at least two adjacent CH groups are replaced by S, NH or O (to form a five-membered aromatic ring). It is furthermore possible for one or both carbon atoms at the point of fusion of bicyclic radicals to the nitrogen atoms (as in indolizinyl).
Particularly appropriate as heteroaryl is furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl,
Heterocycles which are very particularly suitable are thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl and isoquinolyl.
If one of the substituents R(1) to R(6) contains one or more centers of asymmetry, these can have, independently of one another, both the S and R configuration. The compounds can be in the form of optical isomers, of diastereomers, of racemates or as mixtures thereof.
The invention furthermore relates to a process for the preparation of the compounds I, which comprises reacting compounds of the formula II ##STR3## in which R(1) to R(6) have the abovementioned meanings, and L is a leaving group readily amenable to nucleophilic substitution, with guanidine. The activated acid derivatives of the formula II in which L is an alkoxy, preferably a methoxy group or phenoxy group, a phenylthio, methylthio, 2-pyridylthio group, or a nitrogen heterocycle, preferably 1-imidazolyl, are advantageously obtained in a manner known per se from the underlying carbonyl chlorides (formula II, L.dbd.Cl), which in turn can be prepared in a manner known per se from the underlying carboxylic acids (formula II, L.dbd.OH), for example with thionyl chloride. Besides the carbonyl chlorides of the formula II (L.dbd.Cl), other activated acid derivatives of the formula II can also be prepared in a manner known per se directly from the underlying benzoic acid derivatives (formula II, L.dbd.OH), such as, for example, the methyl esters of the formula II with L.dbd.OCH.sub.3 by treating with gaseous HCl in methanol, the imidazolides of the formula II by treatment with carbonyldiimidazole L.dbd.1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1,351-367 (1962)!, the mixed anhydrides II with Cl--COOC.sub.2 H.sub.5 or tosyl chloride in the presence of triethylamine in an inert solvent, as well as the activations of benzoic acids with dicyclohexylcarbodiimide (DCC) or with O-(cyano(ethoxycarbonyl)methylene)amino!-1,1,3,3-tetramethyluronium tetrafluoroborate ("TOTU") Proceedings of the 21. European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991!. A number of suitable methods for preparing activated carboxylic acid derivatives of the formula II is indicated in J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985), page 350, indicated source literature.
The reaction of an activated carboxylic acid derivative of the formula I with guanidine takes place in a manner known per se in a protic or aprotic polar but inert organic solvent. In this connection, for the reaction of the methyl benzoates (II, L.dbd.OMe) with guanidine, methanol, isopropanol or THF have proven suitable at between 20.degree. C. and the boiling point of these solvents. Most reactions of compounds II with salt-free guanidine have advantageously been carried out in inert solvents such as THF, dimethoxyethane, dioxane or isopropanol. However, water can also be used as the solvent.
When L.dbd.Cl, it is advantageous to add an acid trap, for example in the form of excess guanidine to bind the hydrohalic acid.
The introduction of the benzenesulfonamide derivatives which are substituted in the phenyl moiety by sulfur, oxygen or nitrogen nucleophiles takes place by methods known from the literature for nucleophilic substitution on derivatives of 3-nitrobenzoic acid. Halides and trifluoromethanesulfonates have proven suitable as leaving group on the benzoic acid derivative in this substitution. It is advantageous to use a dipolar aprotic solvent such as DMF or TMU, at a temperature from 0.degree. C. to the boiling point of the solvent, preferably from 80.degree. C. to the boiling point of the solvent. Advantageously used as acid trap is an alkali metal or alkaline earth metal salt with an anion of high basicity and low nucleophilicity, for example K.sub.2 CO.sub.3 or Cs.sub.2 CO.sub.3.
The reduction of the nitro compound to the aniline can make use of the standard processes which have been known for some time. Suitable examples are reduction with iron powder in methanol and concentrated aqueous HCl solution.
Surprisingly, the nitro group can also be converted directly into the methanesulfonylamino group using sodium methanesulfinate. To do this, the nitro compound is reacted with sodium methanesulfinate in a dipolar aprotic solvent such as, for example, DMF, TMU or NMP, at a temperature between RT and the boiling point of the solvent, preferably from 80.degree. C. to 160.degree. C.
The introduction of the alkyl or aryl substituents takes place by methods known from the literature of palladium-mediated cross-coupling of aryl halides with, for example, organozinc compounds, organostannanes, organoboronic acids or organoboranes.
Benzoylguanidines I are generally weak bases and are able to bond acid to form salts. Suitable acid addition salts are salts of all pharmacologically suitable acids, for example halides, in particular hydrochlorides, ascorbates, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, p-toluenesulfonates.
Benzoylguanidines are described in U.S. Pat. No. 5 091 394 (HOE 89/F 288) and European Published Specification 0 556 674 (HOE 92/F 034), but in these the substituents do not have the meanings claimed in the present invention. No phenylsulfamide derivatives are described. In addition, the solubility in water of these known benzoylguanidines is unsatisfactory.
These also disclose benzoylguanidines with sulfamoyl substituents R.sub.2 N--SO.sub.2 --; however, no compounds of the type according to the invention which carry an aminosulfonyl group --NR(2)SO.sub.2 --R(1) are disclosed.
The compounds are, as a subsequence of their pharmacological properties, outstandingly suitable as antiarrhythmic pharmaceuticals with a cardioprotective component for the prophylaxis of infarcts and the treatment of infarcts, and for the treatment of angina pectoris, in which case they also preventively inhibit or greatly reduce the pathophysiological processes in the development of ischemia-induced damage, especially in the triggering of ischemia-induced cardiac arrhythmias. Because of their protective effect in pathological hypoxic and ischemic situations, the compounds of the formula I according to the invention can, as a consequence of inhibition of the cellular Na.sup.+ /H.sup.+ exchange mechanism, be used as pharmaceuticals for the treatment of all acute or chronic damage induced by ischemia or disorders induced primarily or secondarily thereby. This relates to their use as pharmaceuticals for surgical interventions, for example in organ transplants, in which case the compounds can be used both to protect the organs in the donor before and during removal, protect removed organs, for example on treatment with or storage thereof in physiological bath liquids, and on transferring to the recipient organism. The compounds are likewise valuable pharmaceuticals which have a protective effect when performing angioplastic surgical interventions, for example on the heart and on peripheral vessels. In accordance with their protective effect on ischemia-induced damage, the compounds are also suitable as pharmaceuticals for the treatment of ischemias of the nervous system, especially the CNS, in which case they are suitable, for example, for treating stroke or cerebral edema. In addition, the compounds of the formula I according to the invention are likewise suitable for treatments of types of shock such as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.
Furthermore, the compounds of the formula I according to the invention are distinguished by a potent inhibitory effect on the proliferation of cells, for example of fibroblast cell proliferation and the proliferation of smooth vascular muscle cells. The compounds of the formula I are therefore suitable as valuable therapeutic agents for diseases in which cell proliferation represents a primary or secondary cause, and can therefore be used as antiatherosclerotics, agents for late complications of diabetes, cancers, fibrotic disorders such as pulmonary fibrosis, liver fibrosis or kidney fibrosis, organ hypertrophies and hyperplasias, especially in prostate hyperplasia and prostate hypertrophy.
The compounds according to the invention are effective inhibitors of the cellular sodium/proton antiporter (Na.sup.+ /H.sup.+ exchanger), which is elevated in numerous disorders (essential hypertension, atherosclerosis, diabetes etc.) also in those cells which are readily accessible to measurements, such as, for example, in erythrocytes, platelets or leukozytes. The compounds according to the invention are therefore suitable as outstanding and simple scientific tools, for example in their use as diagnostic aids for determining and distinguishing certain types of hypertension, but also of atherosclerosis, of diabetes, of proliferative disorders etc. Furthermore, the compounds of the formula I are suitable for preventive therapy to prevent the development of high blood pressure, for example of essential hypertension.
Compared with most of the known compounds, the compounds according to the invention display a significantly improved solubility in water. They are therefore considerably more suitable for i.v. administration.
The compounds according to the invention are distinguished from the known compounds with good solubility in water by their better bioavailabiity and pharmacokinetics.
Pharmaceuticals which contain a compound I can moreover be administered orally, parenterally, intravenously, rectally or by inhalation, with the preferred administration depending on the particular manifestation of the disorder. The compounds I can moreover be used alone or together with pharmaceutical ancillary substances, specifically in veterinary and in human medicine.
The particular ancillary substances suitable for the required pharmaceutical formulation are familiar to the skilled worker on the basis of his expert knowledge. Besides solvents, gel formers, suppository bases, tablet auxiliaries and other active substance vehicles, it is preferable to use for example, antioxidants, dispersants, emulsifiers, antifoams, flavors, preservatives, solubilizers or colorants.
For a form for oral use, the active compounds are mixed with additives suitable for this purpose, such as excipients, stabilizers or inert diluents, and converted by conventional methods into suitable dosage forms such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions. Examples of inert vehicles which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. This preparation can take place either as dry or as wet granules. Examples of suitable oily excipients or solvents are vegetable oils or animal oils, such as sunflower oil or fishliver oil.
For subcutaneous or intravenous administration, the active compounds are converted, if required with the substances customary for this purpose, such as solubilizers, emulsifiers or other ancillary substances, into a solution, suspension or emulsion. Examples of suitable solvents are: water, physiological saline or alcohols, for example ethanol, propanol, glycerol, as well as sugar solutions such as glucose or mannitol solutions or else a mixture of the various solvents mentioned.
Examples of suitable pharmaceutical formulations for administration in the form of aerosols or sprays are solutions, suspensions or emulsions of the active substance of the formula I in a pharmaceutically acceptable solvent such as, in particular, ethanol or water, or a mixture of such solvents. The formulation can also, if required, contain other pharmaceutical ancillary substances such as surfactants, emulsifiers and stabilizers, and a propellant gas. A formulation of this type normally contains the active substance in a concentration of about 0.1 to 10, in particular of about 0.3 to 3% by weight.
The dosage of the active substance of the formula I to be administered, and the frequency of administration, depend on the potency and duration of action of the compounds used; also on the nature and severity of the disease to be treated and on the sex, age, weight and individual response of the mammal to be treated.
On average, the daily dose of a compound of the formula I for a patient weighing about 75 kg is at least 0.001 mg/kg of body weight, preferably at least 0.01 mg/kg of body weight, to a maximum of 10 mg/kg of body weight, preferably up to a maximum of 1 mg/kg of body weight. It is also possible in the case of acute episodes of the is disease, for example immediately after suffering a myocardial infarct, for even higher and, in particular, more frequent doses to be necessary, for example up to 4 single doses per day. Up to 100 mg per day may be necessary, especially on i.v. use, for example for an infarct patient in intensive care.
List of abbreviations:
AIBN .alpha.,.alpha.-azobisisobutyronitrile PA0 Bn benzyl PA0 Brine saturated aqueous NaCl solution PA0 CH.sub.2 Cl.sub.2 dichloromethane PA0 DCI desorption chemical ionization PA0 DIP diisopropyl ether PA0 DMA dimethylacetamide PA0 DME dimethoxyethane PA0 DMF N,N-dimethylformamide PA0 EA ethyl acetate (EtOAc) PA0 El electron impact PA0 eq equivalent PA0 ES elektrospray ionization PA0 Et ethyl PA0 FAB fast atom bombardment PA0 HEP n-heptane PA0 HOAc acetic acid PA0 Me methyl PA0 MeOH methanol PA0 mp melting point PA0 MTB methyl tertiary-butyl ether PA0 NBS N-bromosuccinimide PA0 NMP N-methylpyrrolidone PA0 RT room temperature PA0 THF tetrahydrofuran PA0 TMU N,N,N',N'-tetramethylurea PA0 Tol toluene PA0 CNS central nervous system
Experimental part
General method for the preparation of benzoylguanidines (I)
Variant A: from benzoic acids (II, L.dbd.OH)
0.01M of the benzoic acid derivative of the formula II is dissolved or suspended in 60 ml of anhydrous THF and then 1.78 g (0.011 mol) of carbonyldiimidazole are added. After stirring at RT for 2 hours, 2.95 g (0.05 mol) of guanidine are introduced into the reaction solution. After stirring overnight, the THF is removed by distillation under reduced pressure (rotary evaporator), water is added, the pH is adjusted to 6 to 7 with 2N HCl, and the appropriate benzoylguanidine (formula I) is filtered off. The benzoylguanidines obtained in this way can be converted into corresponding salts by treatment with aqueous, methanolic or ethereal hydrochloric acid or other pharmacologically suitable acids.
General method for the preparation of benzoylguanidines (I)
Variant B: from alkyl benzoates (II, L.dbd.O-alkyl)
5 mmol of the alkyl benzoate of the formula II and 25 mmol of guanidine (free base) are dissolved in 15 ml of isopropanol or suspended in 15 ml of THF and boiled under reflux until conversion is complete (thin-layer check) (typical reaction time 2 to 5 h). The solvent is removed by distillation under reduced pressure (rotary evaporator), the residue is taken up in 300 ml EA and washed 3 x with 50 ml of NaHCO.sub.3 solution each time. It is dried over Na.sub.2 SO.sub.4, the solvent is removed by distillation in vacuo, and chromatography is carried out on silica gel with a suitable mobile phase, for example EA/MeOH 5:1.
(Compare Variant A for salt formation)
General method for the preparation of benzoylguanidines (I)
Variant C: From alkyl benzoates (II, L.dbd.O-alkyl), guanidine liberation in situ
25 mmol of potassium t-butoxide are dissolved in 100 ml of DMF (anhydrous), and 30 mmol of guanidine hydrochloride are added. The mixture is stirred at RT for 1 h and then 5 mmol of the alkyl benzoate of the formula II are added, and the mixture is stirred at RT (typical reaction time 1-24 h) or at 80.degree. C. (typical reaction time 10 minutes to 4 h) until conversion is complete (thin-layer check). The reaction mixture is poured into 500 ml of water, adjusted to pH=8-9 with dilute aqueous HCl solution, stirred for 1 h and filtered with suction. The product is dried in vacuo and, if necessary, chromatographed on silica gel with a suitable mobile phase, for example EA/MeOH 5:1. (Compare Variant A for salt formation)